Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

• ER stress can result from secretory work overload, expression of folding-defective secretory proteins, deprivation of nutrients or oxygen, changes in luminal calcium concentration, and deviation from resting redox state.
• secretory proteins accumulate in unfolded forms within the organelle to trigger a set of intracellular signaling pathways called the unfolded protein response (UPR).
• UPR signaling increases transcription of genes encoding chaperones, oxidoreductases, lipid-biosynthetic enzymes, and ER-associated degradation (ERAD) components.
• the ER stressed state remains too great, and cannot be remedied through the UPR's homeostatic outputs.
• the UPR switches strategies and actively triggers apoptosis.
• Apoptosis of irremediably stressed cells is a quality control strategy that protects multicellular organisms from exposure to immature and damaged secretory proteins. Many deadly human diseases occur if too many cells die through this process. Conversely, many human diseases such as diabetes mellitus and retinopathies proceed from unchecked cell degeneration under ER stress.
• IREla and IREi are ER-transmembrane proteins that become activated when unfolded proteins accumulate within the organelle. IREla is the more widely expressed family member. The bifunctional kinase/endoribonuclease IREla controls entry into the terminal UPR. IRE1 ⁇ senses unfolded proteins through an ER lumenal domain that becomes oligomerized during stress.
• IRE1 ⁇ Under irremediable ER stress, positive feedback signals emanate from the UPR and become integrated and amplified at key nodes to trigger apoptosis.
• IRE1 ⁇ is a key initiator of these pro-apoptotic signals.
• IRE1 ⁇ employs auto-phosphorylation as a timer.
• Remediable ER stress causes low-level, transient auto-phosphorylation that confines RNase activity to XBPl mRNA splicing.
• sustained kinase autophosphorylation causes IRE1 ⁇ ’s RNase to acquire relaxed specificity, causing it to endonucleolytically degrade thousands of ER- localized mRNAs in close proximity to IRE1 ⁇ .
• mRNAs encode secretory proteins being co-translationally translocated (e.g., insulin in ⁇ cells).
• secretory proteins e.g., insulin in ⁇ cells.
• transcripts encoding ER-resident enzymes also become depleted, thus destabilizing the entire ER protein-folding machinery.
• IRE1 ⁇ RNase becomes hyperactive, adaptive signaling through XBPl splicing becomes eclipsed by ER mRNA destruction, which pushes cells into apoptosis.
• a terminal UPR signature tightly controlled by IRE1 ⁇ ’s hyperactive RNase activity causes (1) widespread mRNA degradation at the ER membrane that leads to mitochondrial apoptosis, (2) induction of the pro-oxidant thioredoxin-interacting protein (TXNIP), which activates the NLRP3 inflammasome to produce maturation and secretion of interleukin-1 ⁇ , and consequent sterile inflammation in pancreatic islets leading to diabetes, and (3) degradation of pre-miRNA 17, leading to translational upregulation and cleavage of pre- mitochondrial caspase 2 and stabilization of the mRNA encoding TXNIP.
• TXNIP pro-oxidant thioredoxin-interacting protein
• Retinitis pigmentosa is a clinically and genetically heterogeneous group of inherited retinal disorders characterized by diffuse progressive dysfunction and loss of rod and cone photoreceptors, and retinal pigment epithelium. There are no approved therapies to treat RP patients, who suffer irreversible vision loss. Accumulation of misfolded proteins within the ER appears to be a central causative mechanism in many forms of RP. Mutations in rhodopsin lead to a defective rhodopsin protein that misfolds and accumulates in the ER, causing ER stress.
• the invention provides certain compounds, as well as pharmaceutical composition comprising at least one compound of the invention and at least one pharmaceutically acceptable carrier.
• the invention further provides a method of treating a IRE1 ⁇ -related disease in a subject.
• the invention further provides a method of inhibiting the activity of an IRE1 protein.
• the compound is a compound of formula (Ia), formula (Ib), or formula Ic or a salt solvate enantiomer diastereoisomer isoto olo ue or tautomer
• R 3 is H
• R 3 is selected from the group consisting of H, optionally substituted C 1 -C 8 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 3 - C 8 heterocycloalkyl, optionally substituted C 2 -C 8 heteroalkenyl, optionally substituted benzyl, optionally substituted C 2 -C
• heterocycloalkyl and polycyclic C 3 -C 10 heterocycloalkenyl; wherein Cy is substituted with 0 to‘n’ instances of X, each instance of X being independently selected from the group consisting of H, OH, halide, nitrile, optionally substituted C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, optionally substituted C 1 -C alkoxy, optionally substituted aryl, optionally substituted heteroaryl, and ; each instance of Z, if present, is independently selected from the group consisting of CH and N; m is an integer selected from the group consisting of 0, 1, 2, 3, and 4; n is an integer selected from the group consisting of 0, 1, 2, 3, 4, and 5; and q is an integer selected from the group consisting of 0, 1, 2, 3, 4, and 5.
• each occurrence of optionally substituted aryl or heteroaryl is independently optionally substituted with at least one substituent selected from the group consisting of C b
• each occurrence of optionally substituted aryl or heteroaryl is independently optionally substituted with at least one substituent selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, halo, -CN, -OR c , -N(R c )(R c ), and C 1 -C 6 alkoxycarbonyl, wherein each occurrence of R c is independently H, C 1 -C 6 alkyl, or C 3 -C 8 cycloalkyl.
• R 2 is selected from the group consisting of methyl, ethyl and isopropyl.
• R 3 is selected from the group consisting of:
• R 9 is independently selected from the group consisting of H, oxetanyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 carboxamido alkyl, C 1 -C 6 carboxy alkyl, C 1 -C 6 carboxy(C 1 -C 6 )alkyl alkyl, and C 1 -C 6 cyano alkyl.
• R 3 is selected from the group consisting of: ,
• R 4 is H or–NH 2 .
• R 5 if present, is–F.
• R 7 is selected from the group consisting of:
• each occurrence of R 9 is independently selected from the group consisting of: H, oxetanyl, C 1 -C 8 alkyl, , , ,
• the compound is selected from the group consisting of:
• R' is selected from the rou consistin of:
• the compound is selected from the group consisting of:
• each occurrence of R'' is independently H or C 1 -C 6 alkyl.
• the com ound is selected from the rou consisting of:
• the compound is selected from the group consisting of
• Example 1- Example 232; or a salt, solvate, enantiomer, diastereoisomer, isotopologue, or tautomer thereof.
• the method comprises administering to the subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, solvate, enantiomer, diastereoisomer, or tautomer thereof, and/or a composition of the invention.
• the method comprises contacting the IRE1 protein with an effective amount of a compound, or a pharmaceutically acceptable salt thereof, and/or a composition of the invention.
• the disease is selected from the group consisting of a neurodegenerative disease, a demyelinating disease, cancer, an eye disease, a fibrotic disease, and diabetes.
• the neurodegenerative disease is selected from the group consisting of retinitis pigmentosa, amyotrophic lateral sclerosis, retinal degeneration, macular degeneration, Parkinson’s Disease, Alzheimer’s Disease, Huntington’s Disease, Prion Disease, Creutzfeldt- Jakob Disease, and Kuru.
• the demyelinating disease is selected from the group consisting of Wolfram Syndrome, Pelizaeus-Merzbacher Disease, Transverse Myelitis, Charcot-Marie-Tooth Disease, and Multiple Sclerosis.
• the cancer is multiple myeloma.
• the diabetes is selected from the group consisting of type I diabetes and type II diabetes.
• the eye disease is selected from the group consisting of retinitis pigmentosa, retinal degeneration, macular degeneration, and Wolfram Syndrome.
• the fibrotic disease is selected from the group consisting of idiopathic pulmonary fibrosis (IPF), myocardial infarction, cardiac hypertrophy, heart failure, cirrhosis, acetominophen (TYLENOL®) liver toxicity, hepatitis C liver disease,
• hepatosteatosis fatty liver disease
• hepatic fibrosis hepatosteatosis
• the activity is selected from the group consisting of kinase activity, oligomerization activity, and RNase activity.
• apoptosis of the cell is prevented or minimized.
• the subject is a subject in need of the treatment.
• the present invention relates in part to the unexpected discovery that novel inhibitors of IRE1 ⁇ prevent oligomerization and/or allosterically inhibit its RNase activity.
• the compounds of the invention are compounds of formula (Ia), (Ib) or (Ic): (Ic), or a salt, solvate, enantiomer, diastereoisomer, isotopologue, or tautomer thereof.
• These compounds can be used to treat diseases or disorders associated with ER stress, such as those selected from the group consisting of a neurodegenerative disease, demyelinating disease, cancer, eye disease, fibrotic disease, and diabetes.
• the disease or disorder is a neurodegenerative disease.
• the articles“a” and“an” refer to one or to more than one (i.e. to at least one) of the grammatical object of the article.
• “an element” means one element or more than one element.
• the term“about” is understood by persons of ordinary skill in the art and varies to some extent on the context in which it is used. As used herein when referring to a measurable value such as an amount, a temporal duration, and the like, the term“about” is meant to encompass variations of ⁇ 20% or ⁇ 10%, in certain other embodiments ⁇ 5%, in other embodiments ⁇ 1%, and in yet other embodiments ⁇ 0.1% from the specified value, as such variations are appropriate to perform the disclosed methods.
• a“disorder” in a subject is a state of health in which the subject is able to maintain homeostasis, but in which the subject’s state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the subject’s state of health.
• ED 50 refers to the effective dose of a formulation that produces about 50% of the maximal effect in subjects that are administered that formulation.
• an“effective amount,”“therapeutically effective amount” or “pharmaceutically effective amount” of a compound is that amount of compound that is sufficient to provide a beneficial effect to the subject to which the compound is administered.
• “Instructional material,” as that term is used herein, includes a publication, a recording, a diagram, or any other medium of expression that can be used to communicate the usefulness of the composition and/or compound of the invention in a kit.
• the instructional material of the kit may, for example, be affixed to a container that contains the compound and/or composition of the invention or be shipped together with a container that contains the compound and/or composition. Alternatively, the instructional material may be shipped separately from the container with the intention that the recipient uses the instructional material and the compound cooperatively. Delivery of the instructional material may be, for example, by physical delivery of the publication or other medium of expression
• a“patient” or“subject” may be a human or non-human mammal or a bird.
• Non-human mammals include, for example, livestock and pets, such as ovine, bovine, porcine, canine, feline and murine mammals. In certain other embodiments, the subject is human.
• composition refers to a mixture of at least one compound useful within the invention with a pharmaceutically acceptable carrier.
• the pharmaceutical composition facilitates administration of the compound to a subject.
• the term“pharmaceutically acceptable” refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound useful within the invention, and is relatively non-toxic, i.e., the material may be administered to a subject without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
• the term“pharmaceutically acceptable carrier” means a
• composition or carrier such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful within the invention within or to the subject such that it may perform its intended function.
• a pharmaceutically acceptable material, composition or carrier such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful within the invention within or to the subject such that it may perform its intended function.
• a pharmaceutically acceptable material, composition or carrier such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful within the invention within or to the subject such that it may perform its intended function.
• Such constructs are carried or transported from one
• materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil;
• glycols such as propylene glycol
• polyols such as glycerin, sorbitol, mannitol and polyethylene glycol
• esters such as ethyl oleate and ethyl laurate
• agar buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid;
• “pharmaceutically acceptable carrier” also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound useful within the invention, and are physiologically acceptable to the subject. Supplementary active compounds may also be incorporated into the compositions.
• The“pharmaceutically acceptable carrier” may further include a pharmaceutically acceptable salt of the compound useful within the invention.
• pharmaceutically acceptable salt refers to a salt of the administered compound prepared from pharmaceutically acceptable non-toxic acids and bases, including inorganic acids, inorganic bases, organic acids, inorganic bases, solvates, hydrates, and clathrates thereof.
• the term“pharmaceutical composition” refers to a mixture of at least one compound useful within the invention with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.
• the pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound include, but are not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary and topical administration.
• prevent means avoiding or delaying the onset of symptoms associated with a disease or condition in a subject that has not developed such symptoms at the time the administering of an agent or compound commences.
• Disease, condition and disorder are used interchangeably herein.
• solvate refers to a compound formed by solvation, which is a process of attraction and association of molecules of a solvent with molecules or ions of a solute. As molecules or ions of a solute dissolve in a solvent, they spread out and become surrounded by solvent molecules.
• treat means reducing the frequency or severity with which symptoms of a disease or condition are experienced by a subject by virtue of administering an agent or compound to the subject.
• alkyl by itself or as part of another substituent means, unless otherwise stated, a straight or branched chain hydrocarbon having the number of carbon atoms designated (i.e., C 1 -C 10 means one to ten carbon atoms) and includes straight, branched chain, or cyclic substituent groups. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert butyl, pentyl, neopentyl, hexyl, and cyclopropylmethyl.
• (C 1 -C 6 )alkyl such as, but not limited to, ethyl, methyl, isopropyl, isobutyl, n- pentyl, n-hexyl and cyclopropylmethyl.
• alkylene by itself or as part of another substituent means, unless otherwise stated, a straight or branched hydrocarbon group having the number of carbon atoms designated (i.e., C 1 -C 10 means one to ten carbon atoms) and includes straight, branched chain, or cyclic substituent groups, wherein the group has two open valencies. Examples include methylene, 1,2-ethylene, 1,1-ethylene, 1,1-propylene, 1,2-propylene and 1,3-propylene.
• cycloalkyl by itself or as part of another substituent means, unless otherwise stated, a cyclic chain hydrocarbon having the number of carbon atoms designated (i.e., C3-C6 means a cyclic group comprising a ring group consisting of three to six carbon atoms) and includes straight, branched chain or cyclic substituent groups. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Most preferred is (C 3 -C 6 )cycloalkyl, such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
• alkenyl means, unless otherwise stated, a stable mono-unsaturated or di-unsaturated straight chain or branched chain hydrocarbon group having the stated number of carbon atoms. Examples include vinyl, propenyl (or allyl), crotyl, isopentenyl, butadienyl, 1,3-pentadienyl, 1,4-pentadienyl, and the higher homologs and isomers.
• alkynyl means, unless otherwise stated, a stable straight chain or branched chain hydrocarbon group with a triple carbon-carbon bond, having the stated number of carbon atoms.
• Non- limiting examples include ethynyl and propynyl, and the higher homologs and isomers.
• the term“propargylic” refers to a group exemplified by -CH 2 -C ⁇ CH.
• “homopropargylic” refers to a group exemplified by -CH 2 CH 2 -C ⁇ CH.
• the term“substituted propargylic” refers to a group exemplified by -CR 2 -C ⁇ CR, wherein each occurrence of R is independently H, alkyl, substituted alkyl, alkenyl or substituted alkenyl, with the proviso that at least one R group is not hydrogen.
• substituted homopropargylic refers to a group exemplified by -CR 2 CR 2 -C ⁇ CR, wherein each occurrence of R is independently H, alkyl, substituted alkyl, alkenyl or substituted alkenyl, with the proviso that at least one R group is not hydrogen.
• alkenylene employed alone or in combination with other terms, means, unless otherwise stated, a stable mono-unsaturated or di-unsaturated straight chain or branched chain hydrocarbon group having the stated number of carbon atoms wherein the group has two open valencies.
• alkynylene employed alone or in combination with other terms, means, unless otherwise stated, a stable straight chain or branched chain hydrocarbon group with a triple carbon-carbon bond, having the stated number of carbon atoms wherein the group has two open valencies.
• alkoxy employed alone or in combination with other terms means, unless otherwise stated, an alkyl group having the designated number of carbon atoms, as defined above, connected to the rest of the molecule via an oxygen atom, such as, for example, methoxy, ethoxy, 1-propoxy, 2-propoxy (isopropoxy) and the higher homologs and isomers.
• oxygen atom such as, for example, methoxy, ethoxy, 1-propoxy, 2-propoxy (isopropoxy) and the higher homologs and isomers.
• halo or“halogen” alone or as part of another substituent means, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom, preferably, fluorine, chlorine, or bromine, more preferably, fluorine or chlorine.
• heteroalkyl by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain alkyl group consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized.
• the heteroatom(s) may be placed at any position of the heteroalkyl group, including between the rest of the heteroalkyl group and the fragment to which it is attached, as well as attached to the most distal carbon atom in the heteroalkyl group.
• Up to two heteroatoms may be consecutive, such as, for example, -CH 2 -NH-OCH 3 , or -CH 2 -CH 2 -S-S- CH 3 .
• heteroalkenyl by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain monounsaturated or di unsaturated hydrocarbon group consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. Up to two heteroatoms may be placed consecutively.
• aromatic refers to a carbocycle or heterocycle with one or more polyunsaturated rings and having aromatic character, i.e. having (4n+2) delocalized ⁇ (pi) electrons, where n is an integer.
• aryl employed alone or in combination with other terms, means, unless otherwise stated, a carbocyclic aromatic system containing one or more rings (typically one, two or three rings) wherein such rings may be attached together in a pendent manner, such as a biphenyl, or may be fused, such as naphthalene.
• rings typically one, two or three rings
• naphthalene such as naphthalene.
• examples include phenyl, anthracyl, and naphthyl. Preferred are phenyl and naphthyl, most preferred is phenyl.
• aryl-(C 1 -C 3 )alkyl means a functional group wherein a one to three carbon alkylene chain is attached to an aryl group, e.g., - CH 2 CH 2 -phenyl or -CH 2 - phenyl (benzyl). Preferred is aryl-CH 2 - and aryl-CH(CH 3 )-.
• the term“substituted aryl-(C 1 - C 3 )alkyl” means an aryl-(C 1 -C 3 )alkyl functional group in which the aryl group is substituted. Preferred is substituted aryl(CH 2 )-.
• heteroaryl-(C 1 -C 3 )alkyl means a functional group wherein a one to three carbon alkylene chain is attached to a heteroaryl group, e.g., - CH 2 CH 2 -pyridyl. Preferred is heteroaryl-(CH 2 )-.
• substituted heteroaryl-(C 1 -C 3 )alkyl means a heteroaryl-(C 1 -C 3 )alkyl functional group in which the heteroaryl group is substituted. Preferred is substituted heteroaryl-( CH 2 )-.
• heterocycle or“heterocyclyl” or“heterocyclic” by itself or as part of another substituent means, unless otherwise stated, an unsubstituted or substituted, stable, mono- or multi-cyclic heterocyclic ring system that consists of carbon atoms and at least one heteroatom selected from the group consisting of N, O, and S, and wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen atom may be optionally quaternized.
• the heterocyclic system may be attached, unless otherwise stated, at any heteroatom or carbon atom that affords a stable structure.
• a heterocycle may be aromatic or non-aromatic in nature. In certain other embodiments, the heterocycle is a heteroaryl.
• heteroaryl or“heteroaromatic” refers to a heterocycle having aromatic character.
• a polycyclic heteroaryl may include one or more rings that are partially saturated. Examples include tetrahydroquinoline and 2,3 dihydrobenzofuryl.
• non-aromatic heterocycles include monocyclic groups such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, imidazoline, pyrazolidine, dioxolane, sulfolane, 2,3-dihydrofuran, 2,5-dihydrofuran, tetrahydrofuran, thiophane, piperidine, 1,2,3,6-tetrahydropyridine, 1,4-dihydropyridine, piperazine, morpholine, thiomorpholine, pyran, 2,3-dihydropyran, tetrahydropyran, 1,4-dioxane, 1,3- dioxane, homopiperazine, homopiperidine, 1,3-dioxepane, 4,7-dihydro-1,3-dioxepin and hexamethyleneoxide.
• heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl (such as, but not limited to, 2- and 4-pyrimidinyl), pyridazinyl, thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.
• polycyclic heterocycles include indolyl (such as, but not limited to, 3-, 4- , 5-, 6- and 7-indolyl), indolinyl, quinolyl, tetrahydroquinolyl, isoquinolyl (such as, but not limited to, 1- and 5-isoquinolyl), 1,2,3,4-tetrahydroisoquinolyl, cinnolinyl, quinoxalinyl (such as, but not limited to, 2- and 5-quinoxalinyl), quinazolinyl, phthalazinyl, 1,8-naphthyridinyl, 1,4-benzodioxanyl, coumarin, dihydrocoumarin, 1,5-naphthyridinyl, benzofuryl (such as, but not limited to, 3-, 4-, 5-, 6- and 7-benzofuryl), 2,3-dihydrobenzofuryl, 1,2-benzisoxazolyl, benzothienyl (
• heterocyclyl and heteroaryl moieties are intended to be representative and not limiting.
• substituted means that an atom or group of atoms has replaced hydrogen as the substituent attached to another group.
• the term“substituted” as applied to the rings of these groups refers to any level of substitution, namely mono-, di-, tri-, tetra-, or penta-substitution, where such substitution is permitted.
• the substituents are independently selected, and substitution may be at any chemically accessible position. In certain other embodiments, the substituents vary in number between one and four. In other embodiments, the substituents vary in number between one and three. In yet other embodiments, the substituents vary in number between one and two.
• the substituents are independently selected from the group consisting of C 1 -C 6 alkyl, -OH, C 1 -C 6 alkoxy, halo, amino, acetamido and nitro.
• the carbon chain may be branched, straight or cyclic, with straight being preferred.
• substituted heterocycle and“substituted heteroaryl” as used herein refers to a heterocycle or heteroaryl group having one or more substituents including halogen, CN, OH, NO 2 , amino, alkyl, cycloalkyl, carboxyalkyl (C(O)Oalkyl), trifluoroalkyl such as CF 3 , aryloxy, alkoxy, aryl, or heteroaryl.
• a substituted heterocycle or heteroaryl group may have 1 , 2, 3, or 4 substituents.
• range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible sub-ranges as well as individual numerical values within that range and, when appropriate, partial integers of the numerical values within ranges. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.
• Boc tert-Butyloxycarbonyl
• Cs 2 CO 3 Cesium carbonate
• DCM Dichloromethane
• DEA Diethylamine
• DIPEA N,N- Diisopropylethylamine
• DMF Dimethylformamide
• DMSO Dimethyl sulfoxide
• EDC.HCl N-(3-Dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride
• ER endoplasmic reticulum
• ERAD endoplasmic reticulum-associated degradation
• EtOAc Ethyl acetate
• Et 2 O Diethyl ether
• HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate
• HOBT 1-Hydroxybenzotriazole
• HPLC High-performance liquid chromatography
• IPA 2-Propanol
• KOAc Potassium acetate
• LC-MS Liquid chromatography-mass spectrometry
• LiOH Lithium hydroxide
• MDAP Mass-directed automated purification
• MeCN Acetonitrile
• MeOH Methanol
• MgSO 4 Magnesium sulf
• Pd(dppf)Cl 2 ⁇ DCM [1,1′-Bis(diphenylphosphino)ferrocene]-dichloropalladium(II) DCM complex
• Ph phenyl
• RP Retinitis pigmentosa
• RT Room temperature
• Rt Retention time
• SCX-2 Biotage Isolute - strong cationic ion-exchange resin
• TEA trimethylamine
• TFA trifluoroacetic acid
• THF tetrahydrofuran
• UPLC Ultra-high performance liquid chromatography
• UPR unfolded protein response.
• the invention includes a compound of formula (Ia), formula (Ib) or formula (Ic), or a salt solvate enantiomer diastereoisomer isoto olo ue or tautomer thereof:
• R 2 is selected from the group consisting of H, methyl, ethyl, propyl, CF 3 , CHF 2 , 1-methylcyclopropyl, isopropyl, tert-butyl, and C 3 -C 8 cycloalkyl, wherein each non-H substituent is independently optionally substituted with a single instance of R 7 , with the proviso that, if R 7 is present, R 3 is H;
• R 3 is selected from the group consisting of H, optionally substituted C 1 -C 8 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 3 - C 8 heterocycloalkyl, optionally substituted C 2 -C 8 heteroalkenyl, optionally substituted benzyl, optionally substituted C 2 -C 8 cycloheteroalkenyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl (such as, but not limited to, imidazolyl or pyrazolyl);
• R 4 is selected from the group consisting of -H, -OH, C 1 -C 6 alkoxy, halogen, - NH 2 , and -NHR 8 ;
• each instance of R 5 is independently selected from the group consisting of halide, -OH, C 1 -C 6 alkoxy, optionally substituted phenyl, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, and optionally substituted heterocycloalkyl;
• R 6 is selected from the group consisting of H and optionally substituted C 1 -C 6 alkyl
• R 7 is selected from the group consisting of optionally substituted C 1 -C 8 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 heteroalkyl, optionally substituted C 3 - C 8 heterocycloalkyl, optionally substituted C 2 -C 8 heteroalkenyl, optionally substituted aryl, optionally substituted heteroaryl (such as, but not limited to, imidazolyl or pyrazolyl), and benzyl;
• R 8 is optionally substituted C 1 -C 3 alkyl
• Cy is selected from the group consisting of aryl, heteroaryl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkenyl, C 3 -C 10 heterocycloalkyl, C 3 -C 10 heterocycloalkenyl, polycyclic aryl, polycyclic heteroaryl, polycyclic C 3 -C 10 cycloalkyl, polycyclic C 3 -C 10 cycloalkenyl, polycyclic C 3 -C 10 heterocycloalkyl, and polycyclic C 3 -C 10 heterocycloalkenyl;
• Cy is substituted with 0 to‘n’ instances of X, each instance of X being independently selected from the group consisting of H, OH, halide, nitrile, optionally substituted C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted aryl (such as, but not limited, phenyl), optionally substituted heteroaryl, and each instance of Z, if present, is independently selected from the group consisting of CH and N;
• n is an integer selected from the group consisting of 0, 1, 2, 3, and 4;
• n is an integer selected from the group consisting of 0, 1, 2, 3, 4, and 5; and q is an integer selected from the group consisting of 0, 1, 2, 3, 4, and 5.
• an optionally substituted group is unsubstituted. In other embodiments, an optionally substituted group is substituted with at least substituent contemplated herein.
• each occurrence of optionally substituted aryl or heteroaryl is independently optionally substituted with at least one substituent selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, halo, -CN, -OR b , -N(R b )(R b ), - NO 2 , acyl, and C 1 -C 6 alkoxycarbonyl, wherein each occurrence of R b is independently H, C 1 -C 6 alkyl, or C 3 -C 8 cycloalkyl.
• each occurrence of optionally substituted aryl or heteroaryl is independently optionally substituted with at least one substituent selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, halo, -CN, -OR c , -N(R c )(R c ), and C 1 -C 6 alkoxycarbonyl, wherein each occurrence of R c is independently H, C 1 -C 6 alkyl, or C 3 -C 8 cycloalkyl.
• Cy is selected from the group consisting of: , embodiments, R 1 is rtain embodiments, R 1 is . In certain embodiments, R 1 is tain embodiments, R 1 is , . In certain embodiments, R . In certain embodiments, R In certain embodiments, R In certain embodiments, R 1 is n certain embodiments, R 1 is . In certain embodiments, R 1 is . In certain embodiments, R 1 is n certain embodiments, R 1 is , .
• R 1 is . In certain embodiments, R 1 is . In certain embodiments, R 1 is . In certain embodiments, R 1 is . In certain embodiments, R 1 is . In certain embodiments, R 1 is . In certain embodiments,
• R 1 is .
• R 1 is , .
• R 1 is . In certain embodiments R 1 is . In certain embodiments R 1 is . In certain
• R R .
• R 2 is methyl. In certain embodiments, R 2 is ethyl. In certain embodiments, R 2 is isopropyl.
• R 3 is H. In certain embodiments, R 3 is C 1 -C 8 alkyl. In certain embodiments, R 3 is . In certain embodiments, R 3 is . In certain embodiments, R 3 is . In certain embodiments, R 3 is . In certain embodiments, R 3 is . In certain embodiments, R 3 is . In certain embodiments, R 3 is . In certain embodiments, R 3 is . In certain embodiments, R 3 is . In certain embodiments, R 3 is H. In certain embodiments, R 3 is C 1 -C 8 alkyl. In certain embodiments, R 3 is . In certain embodiments, R 3 is . In certain embodiments, R 3 is . In certain embodiments, R 3 is . In certain embodiments, R 3 is . In certain embodiments, R 3 is C 1 -C 8 alkyl. In certain embodiments, R 3 is . In certain embodiments, R 3 is . In certain embodiments, R 3 is . In certain embodiments, R 3 is . In certain embodiments,
• R 3 is . In certain embodiments R 3 is . In certain embodiments R 3 is . In certain embodiments, R 3 In certain embodiments, R 3 In certain embodiments, R 3 rtain embodiments, R 3 certain embodiments, R 3 . In certain embodiments, R 3 certain embodiments, R 3 . In certain embodiments, R 3
• R 3 is . In certain embodiments, R 3
• R 3 certain embodiments, R 3 In certain embodiments, R 3 rtain embodiments, R 3 . In certain embodiments, R 3
• R 3 is in embodiments, R 3 is
• each occurrence of R 9 is independently selected from the group consisting of H, oxetanyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 carboxamido alkyl, C 1 -C 6 carboxy alkyl, C 1 -C 6 carboxy(C 1 -C 6 )alkyl alk l and C 1 -C 6 cyano alkyl.
• R 4 is H. In certain embodiments, R 4 is -NH 2 .
• R 7 is R 7 is .
• ertain embodiments, R 7 is In certain embodiments, R 7 is . In certain embodiments, ertain embodiments, In certain embodiments, tain embodiments, . In certain embodiments, rtain embodiments, certain embodiments, . In certain embodiments, R 7 is . In certain embodiments, R 7 is . In certain embodiments, R 7 is rtain embodiments, R 7 is . In certain embodiments, tain embodiments, . In certain embodiments, n certain embodiments, . In certain embodiments, R 7 is In certain embodiments, R 7 is . In certain embodiments, R 7 is In certain embodiments, p is an integer from 0-5.
• each occurrence of R 9 is independently selected from the group consisting of H, oxetanyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 carboxamido alkyl, C 1 -C 6 carboxy alkyl, C 1 -C 6 carboxy(C 1 -C 6 )alkyl alkyl, and C 1 -C 6 cyano alkyl.
• each occurrence of R 9 is independently selected from the group consisting of: H, oxetanyl, C 1 -C 8 alkyl, , , ,
• the compound is (Ib'), herein. In certain embodiments, the compound is
• R' is optionally substituted heterocyclyl. In certain embodiments, R' is optionally substituted -NH-(optionally substituted heterocyclyl). In certain embodiments, R' is optionally substituted -N(C 1 -C 6 alkyl)-(optionally substituted heterocyclyl). In certain embodiments, R' is . In certain embodiments, R' is . In certain embodiments, R' is . In certain embodiments,
• R' is tain
• R' is .
• R' is .
• R' is
• R' is . In certain embodiments, R' is .
• the compound is herein R''
• R'' is H or C 1 -C 6 alkyl. In certain embodiments, the comp (Ic''), wherein R'' is H or C 1 -C 6 alkyl. In certain embodiments, R'' is H. In certain embodiments, R''
• R 1 is C 1 -C 6 alkyl. In certain embodiments, R 1 is . In certain embodiments, R 1
• R 1 is .
• R''' is selected from the group consisting of -OH, C 1 -C 6 alkoxy, -NH 2 , -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), and -NH(oxe
• R''' is selected from the group consisting of -OH, C 1 -C 6 alkoxy, -NH 2 , -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), and -NH(oxe
• R'' is H.
• R''' is -OH. In certain embodiments, R''' is -NH 2 . In certain embodiments, R''' is -NHCH 3 . In certain embodiments, R''' is - N(CH 3 ) 2 . In certain embodiments, R''' is -NHCH 2 CH 2 F. In certain embodiments, R''' is - N(Me)CH 2 CH 2 F. In certain embodiments, R''' is -NHCH 2 CHF 2 . In certain embodiments, R''' is -N(Me)CH 2 CHF 2 . In certain embodiments, R''' is -NHCH 2 CF 3 .
• the compound is selected from the group consisting of:
• Example 1 3- ⁇ 4-[8-amino-3-methyl-5-(piperazine-1-carbonyl)imidazo[1,5-a]pyrazin-1- yl]naphthalen-1-yl ⁇ -1-[3-(trifluoromethyl)phenyl]urea;
• Example 2 3- ⁇ 4-[8-amino-5-(4-aminopiperidine-1-carbonyl)-3-methylimidazo[1,5- a]pyrazin-1-yl]naphthalen-1-yl ⁇ -1-[3-(trifluoromethyl)phenyl]urea);
• Example 3 8-amino-3-methyl-N-(piperidin-4-yl)-1-[4-( ⁇ [3- (trifluoromethyl)phenyl]carbamoyl ⁇ amino)naphthalen-1-yl]imidazo[1,5-a]pyrazine-5- carboxamide;
• Example 4 3-(4- ⁇ 8-amino-5-[(3R)-3-aminopiperidine-1-carbonyl]-3-methylimidazo[1,5- a]pyrazin-1-yl ⁇ naphthalen-1-yl)-1-[3-(trifluoromethyl)phenyl]urea;
• Example 5 3-(4- ⁇ 8-amino-5-[(3S)-3-aminopiperidine-1-carbonyl]-3-methylimidazo[1,5- a]pyrazin-1-yl ⁇ naphthalen-1-yl)-1-[3-(trifluoromethyl)phenyl]urea);
• Example 6 8-amino-3-methyl-N-[(3R)-piperidin-3-yl]-1-[4-( ⁇ [3- (trifluoromethyl)phenyl]carbamoyl ⁇ amino)naphthalen-1-yl]imidazo[1,5-a]pyrazine-5- carboxamide;
• Example 7 8-amino-3-methyl-N-(piperidin-3-yl)-1-[4-( ⁇ [3- (trifluoromethyl)phenyl]carbamoyl ⁇ amino)naphthalen-1-yl]imidazo[1,5-a]pyrazine-5- carboxamide;
• Example 8 8-amino-3-methyl-N-[(3S)-1-methylpiperidin-3-yl]-1-[4-( ⁇ [3- (trifluoromethyl)phenyl]carbamoyl ⁇ amino)naphthalen-1-yl]imidazo[1,5-a]pyrazine-5- carboxamide;
• Example 9 8-amino-3-methyl-N-[(3R)-1-methylpiperidin-3-yl]-1-[4-( ⁇ [3- (trifluoromethyl)phenyl]carbamoyl ⁇ amino)naphthalen-1-yl]imidazo[1,5-a]pyrazine-5- carboxamide;
• Example 10 3- ⁇ 4-[8-amino-3-methyl-5-(4-methylpiperazine-1-carbonyl)imidazo[1,5- a]pyrazin-1-yl]naphthalen-1-yl ⁇ -1-[3-(trifluoromethyl)phenyl]urea;
• Example 11 3- ⁇ 4-[8-amino-3-methyl-5-(piperidin-4-ylmethyl)imidazo[1,5-a]pyrazin-1- yl]naphthalen-1-yl ⁇ -1-[3-(trifluoromethyl)phenyl]urea;
• Example 12 3- ⁇ 4-[8-amino-3-methyl-5-(piperazin-1-ylmethyl)imidazo[1,5-a]pyrazin-1- yl]naphthalen-1-yl ⁇ -1-[3-(trifluoromethyl)phenyl]urea;
• Example 13 3-(4- ⁇ 8-amino-5-[(4-aminopiperidin-1-yl)methyl]-3-methylimidazo[1,5- a]pyrazin-1-yl ⁇ naphthalen-1-yl)-1-[3-(trifluoromethyl)phenyl]urea;
• Example 14 3-[4-(8-amino-3-methyl-5- ⁇ [(piperidin-4-yl)amino]methyl ⁇ imidazo[1,5- a]pyrazin-1-yl)naphthalen-1-yl]-1-[3-(trifluoromethyl)phenyl]urea;
• Example 15 3-[4-(8-amino-5- ⁇ [(3R)-3-aminopiperidin-1-yl]methyl ⁇ -3-methylimidazo[1,5- a]pyrazin-1-yl)naphthalen-1-yl]-1-[3-(trifluoromethyl)phenyl]urea;
• Example 16 3-[4-(8-amino-5- ⁇ [(3S)-3-aminopiperidin-1-yl]methyl ⁇ -3-methylimidazo[1,5- a]pyrazin-1-yl)naphthalen-1-yl]-1-[3-(trifluoromethyl)phenyl]urea;
• Example 17 3-[4-(8-amino-3-methyl-5- ⁇ [(piperidin-3-yl)amino]methyl ⁇ imidazo[1,5- a]pyrazin-1-yl)naphthalen-1-yl]-1-[3-(trifluoromethyl)phenyl]urea;
• Example 18 3- ⁇ 4-[8-amino-3-methyl-5-( ⁇ [(3S)-piperidin-3-yl]amino ⁇ methyl)imidazo[1,5- a]pyrazin-1-yl]naphthalen-1-yl ⁇ -1-[3-(trifluoromethyl)phenyl]urea;
• Example 19 3-(4- ⁇ 8-amino-3-methyl-5-[(4-methylpiperazin-1-yl)methyl]imidazo[1,5- a]pyrazin-1-yl ⁇ naphthalen-1-yl)-1-[3-(trifluoromethyl)phenyl]urea;
• Example 20 3- ⁇ 4-[8-amino-3-ethyl-5-(piperazin-1-ylmethyl)imidazo[1,5-a]pyrazin-1- yl]naphthalen-1-yl ⁇ -1-[3-(trifluoromethyl)phenyl]urea;
• Example 21 3- ⁇ 4-[8-amino-5-(piperazin-1-ylmethyl)-3-(propan-2-yl)imidazo[1,5-a]pyrazin- 1-yl]naphthalen-1-yl ⁇ -1-[3-(trifluoromethyl)phenyl]urea;
• Example 22 3-(4- ⁇ 8-amino-3-ethyl-5-[(4-methylpiperazin-1-yl)methyl]imidazo[1,5- a]pyrazin-1-yl ⁇ naphthalen-1-yl)-1-[3-(trifluoromethyl)phenyl]urea;
• Example 23 3-[4-(8-amino-3-methyl-5- ⁇ [4-(methylamino)piperidin-1- yl]methyl ⁇ imidazo[1,5-a]pyrazin-1-yl)naphthalen-1-yl]-1-[3-(trifluoromethyl)phenyl]urea;
• Example 24 3-[4-(8-amino-3-methyl-5- ⁇ [(3R)-3-methylpiperazin-1-yl]methyl ⁇ imidazo[1,5- a]pyrazin-1-yl)naphthalen-1-yl]-1-[3-(trifluoromethyl)phenyl]urea;
• Example 25 3-[4-(8-amino-3-methyl-5- ⁇ [(3S)-3-methylpiperazin-1-yl]methyl ⁇ imidazo[1,5- a]pyrazin-1-yl)naphthalen-1-yl]-1-[3-(trifluoromethyl)phenyl]urea;
• Example 26 3-[4-(8-amino-5- ⁇ [(3R,5S)-3,5-dimethylpiperazin-1-yl]methyl ⁇ -3- methylimidazo[1,5-a]pyrazin-1-yl)naphthalen-1-yl]-1-[3-(trifluoromethyl)phenyl]urea;
• Example 27 3-[4-(8-amino-3-ethyl-5- ⁇ [(3R)-3-methylpiperazin-1-yl]methyl ⁇ imidazo[1,5- a]pyrazin-1-yl)naphthalen-1-yl]-1-[3-(trifluoromethyl)phenyl]urea;
• Example 28 3-[4-(8-amino-3-ethyl-5- ⁇ [(3S)-3-methylpiperazin-1-yl]methyl ⁇ imidazo[1,5- a]pyrazin-1-yl)naphthalen-1-yl]-1-[3-(trifluoromethyl)phenyl]urea;
• Example 29 3- ⁇ 4-[8-amino-5-(1,4-diazepan-1-ylmethyl)-3-methylimidazo[1,5-a]pyrazin-1- yl]naphthalen-1-yl ⁇ -1-[3-(trifluoromethyl)phenyl]urea;
• Example 30 3-[4-(8-amino-5- ⁇ 2,5-diazabicyclo[2.2.1]heptan-2-ylmethyl ⁇ -3- methylimidazo[1,5-a]pyrazin-1-yl)naphthalen-1-yl]-1-[3-(trifluoromethyl)phenyl]urea;
• Example 31 3-[4-(8-amino-3-methyl-5- ⁇ octahydropyrrolo[3,4-c]pyrrol-2- ylmethyl ⁇ imidazo[1,5-a]pyrazin-1-yl)naphthalen-1-yl]-1-[3-(trifluoromethyl)phenyl]urea;
• Example 32 3- ⁇ 4-[8-amino-3-methyl-5-(piperazin-1-ylmethyl)imidazo[1,5-a]pyrazin-1- yl]naphthalen-1-yl ⁇ -1-(3-fluorophenyl)urea;
• Example 33 3- ⁇ 4-[8-amino-3-methyl-5-(piperazin-1-ylmethyl)imidazo[1,5-a]pyrazin-1- yl]naphthalen-1-yl ⁇ -1-(3-methylphenyl)urea;
• Example 34 3- ⁇ 4-[8-amino-3-methyl-5-(piperazin-1-ylmethyl)imidazo[1,5-a]pyrazin-1-yl]- 3-fluorophenyl ⁇ -1-[3-(trifluoromethyl)phenyl]urea;
• Example 35 3- ⁇ 4-[8-amino-3-ethyl-5-(piperazin-1-ylmethyl)imidazo[1,5-a]pyrazin-1-yl]-3- fluorophenyl ⁇ -1-[3-(trifluoromethyl)phenyl]urea;
• Example 36 N-(4-(8-amino-3-isopropyl-5-(piperazin-1-ylmethyl)imidazo[1,5-a]pyrazin-1- yl)-2-fluorophenyl)-1-(2-chlorophenyl)methanesulfonamide;
• Example 37 3-isopropyl-1-(4-((7-methyl-1H-benzo[d]imidazol-2-yl)methyl)naphthalen-1- yl)-5-(piperazin-1-ylmethyl)imidazo[1,5-a]pyrazin-8-amine;
• Example 38 2- ⁇ 4-[8-amino-3-methyl-5-(piperazin-1-ylmethyl)imidazo[1,5-a]pyrazin-1- yl]naphthalen-1-yl ⁇ -N-[3-(trifluoromethyl)phenyl]acetamide;
• Example 39 3- ⁇ 4-[8-amino-3-methyl-5-(1,2,5,6-tetrahydropyridin-3-yl)imidazo[1,5- a]pyrazin-1-yl]naphthalen-1-yl ⁇ -1-[3-(trifluoromethyl)phenyl]urea;
• Example 40 3- ⁇ 4-[8-amino-3-methyl-5-(piperidin-3-yl)imidazo[1,5-a]pyrazin-1- yl]naphthalen-1-yl ⁇ -1-[3-(trifluoromethyl)phenyl]urea;
• Example 41 3- ⁇ 4-[8-amino-3-methyl-5-(1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,5- a]pyrazin-1-yl]naphthalen-1-yl ⁇ -1-[3-(trifluoromethyl)phenyl]urea;
• Example 42 3- ⁇ 4-[8-amino-3-methyl-5-(1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,5- a]pyrazin-1-yl]-3-fluorophenyl ⁇ -1-[3-(trifluoromethyl)phenyl]urea;
• Example 43 3- ⁇ 4-[5-(1-acetyl-1,2,5,6-tetrahydropyridin-3-yl)-8-amino-3- methylimidazo[1,5-a]pyrazin-1-yl]naphthalen-1-yl ⁇ -1-[3-(trifluoromethyl)phenyl]urea;
• Example 44 3- ⁇ 4-[5-(1-acetylpiperidin-3-yl)-8-amino-3-methylimidazo[1,5-a]pyrazin-1- yl]naphthalen-1-yl ⁇ -1-[3-(trifluoromethyl)phenyl]urea;
• Example 45 3- ⁇ 4-[5-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-8-amino-3- methylimidazo[1,5-a]pyrazin-1-yl]-3-fluorophenyl ⁇ -1-[3-(trifluoromethyl)phenyl]urea;
• Example 46 3- ⁇ 4-[8-amino-5-(cyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1- yl]naphthalen-1-yl ⁇ -1-[3-(trifluoromethyl)phenyl]urea;
• Example 47 3- ⁇ 4-[8-amino-3-methyl-5-(1-methyl-1,2,3,6-tetrahydropyridin-4- yl)imidazo[1,5-a]pyrazin-1-yl]naphthalen-1-yl ⁇ -1-[3-(trifluoromethyl)phenyl]urea;
• Example 48 3- ⁇ 4-[8-amino-3-methyl-5-(pyridin-3-yl)imidazo[1,5-a]pyrazin-1- yl]naphthalen-1-yl ⁇ -1-[3-(trifluoromethyl)phenyl]urea;
• Example 49 3-(4- ⁇ 8-amino-3-methyl-5-[1-(prop-2-enoyl)-1,2,3,6-tetrahydropyridin-4- yl]imidazo[1,5-a]pyrazin-1-yl ⁇ naphthalen-1-yl)-1-[3-(trifluoromethyl)phenyl]urea;
• Example 50 3- ⁇ 4-[8-amino-5-(4-aminophenyl)-3-methylimidazo[1,5-a]pyrazin-1- yl]naphthalen-1-yl ⁇ -1-[3-(trifluoromethyl)phenyl]urea;
• Example 51 3- ⁇ 4-[8-amino-3-methyl-5-(1-methyl-1H-pyrazol-4-yl)imidazo[1,5-a]pyrazin- 1-yl]naphthalen-1-yl ⁇ -1-[3-(trifluoromethyl)phenyl]urea;
• Example 52 3- ⁇ 4-[8-amino-5-(1,5-dimethyl-1H-pyrazol-4-yl)-3-methylimidazo[1,5- a]pyrazin-1-yl]naphthalen-1-yl ⁇ -1-[3-(trifluoromethyl)phenyl]urea;
• Example 53 3- ⁇ 4-[8-amino-5-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methylimidazo[1,5- a]pyrazin-1-yl]naphthalen-1-yl ⁇ -1-[3-(trifluoromethyl)phenyl]urea;
• Example 54 3-(4- ⁇ 8-amino-3-methyl-5-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]imidazo[1,5- a]pyrazin-1-yl ⁇ naphthalen-1-yl)-1-[3-(trifluoromethyl)phenyl]urea;
• Example 55 3- ⁇ 4-[8-amino-3-methyl-5-(1,2,3,4-tetrahydroisoquinolin-5-yl)imidazo[1,5- a]pyrazin-1-yl]naphthalen-1-yl ⁇ -1-[3-(trifluoromethyl)phenyl]urea;
• Example 56 3- ⁇ 4-[8-amino-5-(2-aminopyridin-4-yl)-3-methylimidazo[1,5-a]pyrazin-1- yl]naphthalen-1-yl ⁇ -1-[3-(trifluoromethyl)phenyl]urea;
• Example 57 2-(4-(8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin- 1-yl)naphthalen-1-yl)-N-(3-(trifluoromethyl)phenyl)acetamide;
• Example 59 2-(4- ⁇ 8-amino-5-[4-(methylamino)cyclohex-1-en-1-yl]-3-(propan-2- yl)imidazo[1,5-a]pyrazin-1-yl ⁇ naphthalen-1-yl)-N-[3-(trifluoromethyl)phenyl]acetamide;
• Example 60 2-(4- ⁇ 8-amino-3-methyl-5-[4-(methylamino)cyclohex-1-en-1-yl]imidazo[1,5- a]pyrazin-1-yl ⁇ naphthalen-1-yl)-N-[3-(trifluoromethyl)phenyl]acetamide;
• Example 61 2-(4- ⁇ 8-amino-3-methyl-5-[4-(methylamino)cyclohex-1-en-1-yl]imidazo[1,5- a]pyrazin-1-yl ⁇ -3-fluorophenyl)-N-[3-(trifluoromethyl)phenyl]acetamide;
• Example 62 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5- a]pyrazin-1-yl)naphthalen-1-yl)-N-phenylacetamide;
• Example 63 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5- a]pyrazin-1-yl)-3-fluorophenyl)-N-(3-fluorophenyl)acetamide;
• Example 64 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5- a]pyrazin-1-yl)naphthalen-1-yl)-N-(3-fluorophenyl)acetamide;
• Example 65 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5- a]pyrazin-1-yl)naphthalen-1-yl)-N-(3-fluoro-5-methoxyphenyl)acetamide;
• Example 66 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5- a]pyrazin-1-yl)-3-fluorophenyl)-N-phenylacetamide;
• Example 67 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5- a]pyrazin-1-yl)naphthalen-1-yl)-N-(3-cyano-5-fluorophenyl)acetamide;
• Example 68 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5- a]pyrazin-1-yl)naphthalen-1-yl)-N-(pyridin-2-yl)acetamide;
• Example 69 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5- a]pyrazin-1-yl)naphthalen-1-yl)-N-(5-methoxypyridin-3-yl)acetamide;
• Example 71 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5- a]pyrazin-1-yl)naphthalen-1-yl)-N-(3-methoxyphenyl)acetamide;
• Example 72 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5- a]pyrazin-1-yl)naphthalen-1-yl)-N-(pyridin-3-yl)acetamide;
• Example 73 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5- a]pyrazin-1-yl)naphthalen-1-yl)-N-(pyrazin-2-yl)acetamide;
• Example 74 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5- a]pyrazin-1-yl)naphthalen-1-yl)-N-(thiazol-5-yl)acetamide;
• Example 76 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5- a]pyrazin-1-yl)naphthalen-1-yl)-N-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)acetamide;
• Example 77 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5- a]pyrazin-1-yl)naphthalen-1-yl)-N-(1-methyl-1H-pyrazol-4-yl)acetamide;
• Example 78 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5- a]pyrazin-1-yl)naphthalen-1-yl)-N-(3,4-dimethoxyphenyl)acetamide;
• Example 79 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5- a]pyrazin-1-yl)naphthalen-1-yl)-N-(pyrimidin-5-yl)acetamide;
• Example 80 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5- a]pyrazin-1-yl)naphthalen-1-yl)-N-(5-fluoropyridin-3-yl)acetamide;
• Example 81 2-(5-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5- a]pyrazin-1-yl)naphthalen-1-yl)-N-(3-fluorophenyl)acetamide;
• Example 82 2-(5-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5- a]pyrazin-1-yl)naphthalen-1-yl)-N-phenylacetamide;
• Example 83 3- ⁇ 4-[8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin- 1-yl]naphthalen-1-yl ⁇ -1-[3-(trifluoromethyl)phenyl]urea;
• Example 84 3-(4- ⁇ 8-amino-3-methyl-5-[4-(methylamino)cyclohex-1-en-1-yl]imidazo[1,5- a]pyrazin-1-yl ⁇ naphthalen-1-yl)-1-[3-(trifluoromethyl)phenyl]urea;
• Example 85 1-(4-(8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-ethylimidazo[1,5-a]pyrazin-1- yl)naphthalen-1-yl)-3-(3-(trifluoromethyl)phenyl)urea;
• Example 86 3- ⁇ 4-[8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-(propan-2-yl)imidazo[1,5- a]pyrazin-1-yl]naphthalen-1-yl ⁇ -1-[3-(trifluoromethyl)phenyl]urea;
• Example 87 1-(4-(8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin- 1-yl)naphthalen-1-yl)-3-phenylurea;
• Example 88 3- ⁇ 4-[8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin- 1-yl]naphthalen-1-yl ⁇ -1-[3,5-bis(trifluoromethyl)phenyl]urea;
• Example 89 3- ⁇ 4-[8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin- 1-yl]naphthalen-1-yl ⁇ -1-(3,5-dimethylphenyl)urea;
• Example 90 3- ⁇ 4-[8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin- 1-yl]naphthalen-1-yl ⁇ -1-[4-chloro-3-(trifluoromethyl)phenyl]urea;
• Example 91 1-(4-(8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin- 1-yl)naphthalen-1-yl)-3-benzylurea;
• Example 92 3- ⁇ 4-[8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin- 1-yl]naphthalen-1-yl ⁇ -1-[(4-methylphenyl)methyl]urea;
• Example 93 1-(4-(8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin- 1-yl)naphthalen-1-yl)-3-(2-chloro-5-(trifluoromethyl)phenyl)urea;
• Example 94 1- ⁇ 4-[8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin- 1-yl]naphthalen-1-yl ⁇ -3-(5-chloro-2-methoxyphenyl)urea;
• Example 97 3- ⁇ 4-[8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin- 1-yl]naphthalen-1-yl ⁇ -1-(3-fluorophenyl)urea;
• Example 99 1- ⁇ 4-[8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin- 1-yl]naphthalen-1-yl ⁇ -3-(2-methoxyphenyl)urea;
• Example 101 N-(4- ⁇ 8-amino-3-methyl-1-[4-( ⁇ [3- (trifluoromethyl)phenyl]carbamoyl ⁇ amino)naphthalen-1-yl]imidazo[1,5-a]pyrazin-5- yl ⁇ cyclohex-3-en-1-yl)acetamide;
• Example 102 1- ⁇ 4-[8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5- a]pyrazin-1-yl]naphthalen-1-yl ⁇ -3- ⁇ 4-[(4-methylpiperazin-1-yl)methyl]phenyl ⁇ urea;
• Example 105 1- ⁇ 4-[8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5- a]pyrazin-1-yl]-3-fluorophenyl ⁇ -3- ⁇ 4-[(4-methylpiperazin-1-yl)methyl]phenyl ⁇ urea;
• Example 106 3-(4- ⁇ 8-amino-3-ethyl-5-[4-(methylamino)cyclohex-1-en-1-yl]imidazo[1,5- a]pyrazin-1-yl ⁇ naphthalen-1-yl)-1-[3-(trifluoromethyl)phenyl]urea;
• Example 107 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1- yl)imidazo[1,5-a]pyrazin-1-yl)naphthalen-1-yl)-3-(3-(trifluoromethyl)phenyl)urea;
• Example 109 3-(4- ⁇ 8-amino-5-[4-(methylamino)cyclohex-1-en-1-yl]-3-(propan-2- yl)imidazo[1,5-a]pyrazin-1-yl ⁇ -3-fluorophenyl)-1-[3-(trifluoromethyl)phenyl]urea;
• Example 111 3-(4- ⁇ 8-amino-3-methyl-5-[4-(methylamino)cyclohex-1-en-1-yl]imidazo[1,5- a]pyrazin-1-yl ⁇ -3-methylphenyl)-1-[3-(trifluoromethyl)phenyl]urea;
• Example 112 3-(4- ⁇ 8-amino-3-methyl-5-[4-(methylamino)cyclohex-1-en-1-yl]imidazo[1,5- a]pyrazin-1-yl ⁇ -2-methylphenyl)-1-[3-(trifluoromethyl)phenyl]urea;
• Example 113 3-(4- ⁇ 8-amino-3-methyl-5-[4-(methylamino)cyclohex-1-en-1-yl]imidazo[1,5- a]pyrazin-1-yl ⁇ -5-fluoro-2-methylphenyl)-1-[3-(trifluoromethyl)phenyl]urea;
• Example 116 3-(4- ⁇ 8-amino-3-methyl-5-[4-(methylamino)cyclohex-1-en-1-yl]imidazo[1,5- a]pyrazin-1-yl ⁇ naphthalen-1-yl)-1-(3-fluorophenyl)urea;
• Example 117 3-(4- ⁇ 8-amino-3-ethyl-5-[4-(methylamino)cyclohex-1-en-1-yl]imidazo[1,5- a]pyrazin-1-yl ⁇ naphthalen-1-yl)-1-(3-fluorophenyl)urea;
• Example 119 3-(4- ⁇ 8-amino-5-[4-(methylamino)cyclohex-1-en-1-yl]-3-(propan-2- yl)imidazo[1,5-a]pyrazin-1-yl ⁇ naphthalen-1-yl)-1-(3-methylphenyl)urea;
• Example 120 3-(4- ⁇ 8-amino-5-[4-(methylamino)cyclohex-1-en-1-yl]-3-(propan-2- yl)imidazo[1,5-a]pyrazin-1-yl ⁇ naphthalen-1-yl)-1-(3-fluorophenyl)urea;
• Example 121 1-(4-(8-Amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1- yl)imidazo[1,5-a] pyrazin-1-yl)naphthalen-1-yl)-3-phenylurea;
• Example 122 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1- yl)imidazo[1,5-a]pyrazin-1-yl)naphthalen-1-yl)-3-(pyridin-3-yl)urea;
• Example 123 1-(5-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1- yl)imidazo[1,5-a]pyrazin-1-yl)naphthalen-1-yl)-3-(3-fluorophenyl)urea;
• Example 124 1-(5-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1- yl)imidazo[1,5-a]pyrazin-1-yl)naphthalen-1-yl)-3-(3-(trifluoromethyl)phenyl)urea;
• Example 125 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1- yl)imidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)urea;
• Example 126 1-(4-(8-amino-3-ethyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5- a]pyrazin-1-yl)-3-fluorophenyl)-3-(3-fluorophenyl)urea;
• Example 127 1-(5-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1- yl)imidazo[1,5-a]pyrazin-1-yl)naphthalen-1-yl)-3-phenylurea;
• Example 128 1-(5-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1- yl)imidazo[1,5-a]pyrazin-1-yl)naphthalen-1-yl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)urea;
• Example 129 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1- yl)imidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl)-3-(3-fluorophenyl)urea;
• Example 130 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1- yl)imidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl)-3-phenylurea;
• Example 132 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1- yl)imidazo[1,5-a]pyrazin-1-yl)-3-methoxyphenyl)-3-(3-fluorophenyl)urea;
• Example 133 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1- yl)imidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-3-phenylurea;
• Example 135 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1- yl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-3-(pyridin-3-yl)urea;
• Example 136 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1- yl)imidazo[1,5-a]pyrazin-1-yl)naphthalen-1-yl)-3-(3-cyano-5-fluorophenyl)urea;
• Example 137 1-(5-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1- yl)imidazo[1,5-a]pyrazin-1-yl)isoquinolin-8-yl)-3-(3-fluorophenyl)urea;
• Example 138 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1- yl)imidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl)-3-(pyridin-3-yl)urea;
• Example 139 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1- yl)imidazo[1,5-a]pyrazin-1-yl)naphthalen-1-yl)-3-benzylurea;
• Example 140 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1- yl)imidazo[1,5-a]pyrazin-1-yl)naphthalen-1-yl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)urea;
• Example 141 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1- yl)imidazo[1,5-a]pyrazin-1-yl)naphthalen-1-yl)-3-(3-methoxyphenyl)urea;
• Example 142 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1- yl)imidazo[1,5-a]pyrazin-1-yl)naphthalen-1-yl)-3-(3-cyanophenyl)urea;
• Example 143 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1- yl)imidazo[1,5-a]pyrazin-1-yl)naphthalen-1-yl)-3-(3,4-dimethoxyphenyl)urea;
• Example 144 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1- yl)imidazo[1,5-a]pyrazin-1-yl)naphthalen-1-yl)-3-(pyridin-4-yl)urea;
• Example 145 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1- yl)imidazo[1,5-a]pyrazin-1-yl)naphthalen-1-yl)-3-(4-fluorophenyl)urea;
• Example 146 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1- yl)imidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl)-3-(3-fluoro-5-methoxyphenyl)urea;
• Example 147 1-(4-(8-amino-3-methyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5- a]pyrazin-1-yl)naphthalen-1-yl)-3-(pyridin-3-yl)urea;
• Example 148 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1- yl)imidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl)-3-(5-methoxypyridin-3-yl)urea;
• Example 149 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1- yl)imidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl)-3-(5-fluoropyridin-3-yl)urea;
• Example 150 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1- yl)imidazo[1,5-a]pyrazin-1-yl)naphthalen-1-yl)-3-(thiophen-3-yl)urea;
• Example 153 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1- yl)imidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-3-(pyridin-3-yl)urea;
• Example 156 3-Isopropyl-1-(4-((7-methyl-1H-benzo[d]imidazol-2-yl)methyl)naphthalen-1- yl)-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-8-amine;
• Example 158 1-(4-((1H-benzo[d]imidazol-2-yl)methyl)-2-fluorophenyl)-3-isopropyl-5-(4- (methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-8-amine;
• Example 159 1-(4-((1H-benzo[d]imidazol-2-yl)methyl)naphthalen-1-yl)-3-isopropyl-5-(4- (methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-8-amine;
• Example 164 2-((4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1- yl)imidazo[1,5-a]pyrazin-1-yl)naphthalen-1-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;
• Example 165 1-(4-((7-fluoro-1H-benzo[d]imidazol-2-yl)methyl)naphthalen-1-yl)-3- isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-8-amine;
• Example 168 3-Isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)-1-(4-((5-phenyl-1H- imidazol-2-yl)methyl)naphthalen-1-yl)imidazo[1,5-a]pyrazin-8-amine;
• Example 171 N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1- yl)imidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl)benzenesulfonamide;
• Example 172 N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1- yl)imidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl)-3-fluorobenzenesulfonamide;
• Example 173 N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1- yl)imidazo[1,5-a]pyrazin-1-yl)naphthalen-1-yl)-1-(2-chlorophenyl)methanesulfonamide;
• Example 174 N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1- yl)imidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl)-2-chlorobenzenesulfonamide;
• Example 176 N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1- yl)imidazo[1,5-a]pyrazin-1-yl)naphthalen-1-yl)-3-fluorobenzenesulfonamide;
• Example 178 N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1- yl)imidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6- sulfonamide;
• Example 179 N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1- yl)imidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide;
• Example 180 N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1- yl)imidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl)-1-(2-chlorophenyl)methanesulfonamide;
• Example 181 N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1- yl)imidazo[1,5-a]pyrazin-1-yl)naphthalen-1-yl)-2-chlorobenzenesulfonamide;
• Example 182 N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1- yl)imidazo[1,5-a]pyrazin-1-yl)naphthalen-1-yl)-1-(3-fluorophenyl)methanesulfonamide;
• Example 183 N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1- yl)imidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl)-1-phenylmethanesulfonamide;
• Example 193 N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1- yl)imidazo[1,5-a]pyrazin-1-yl)naphthalen-1-yl)-3-(trifluoromethyl)benzenesulfonamide;
• Example 194 N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1- yl)imidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl)-3-(trifluoromethyl)benzenesulfonamide;
• Example 195 N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1- yl)imidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl)-2
• Example 200 N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1- yl)imidazo[1,5-a]pyrazin-1-yl)naphthalen-1-yl)-1-(3-methoxyphenyl)methanesulfonamide;
• Example 201 N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1- yl)imidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl)-1-(3-methoxyphenyl)methanesulfonamide;
• Example 202 N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1- yl)imidazo[1,5-a]pyrazin-1-yl)naphthalen-1
• Example 205 (3S)-1-[(8-amino-1- ⁇ 4-[(4-methyl-1H-1,3-benzodiazol-2- yl)methyl]naphthalen-1-yl ⁇ -3-(propan-2-yl)imidazo[1,5-a]pyrazin-5-yl)methyl]piperidin-3- amine;
• Example 206 1- ⁇ 4-[(1-methyl-1H-1,3-benzodiazol-2-yl)methyl]naphthalen-1-yl ⁇ -5-[4- (methylamino)cyclohex-1-en-1-yl]-3-(propan-2-yl)imidazo[1,5-a]pyrazin-8-amine;
• Example 221 1-(4-((1H-Benzo[d]imidazol-2-yl)methyl)naphthalen-1-yl)-8-chloro-3- (piperazin-1-ylmethyl)imidazo[1,5-a]pyrazine;
• Example 231 N-(4-(8-amino-5-(4-((2-fluoroethyl)amino)cyclohex-1-en-1-yl)-3- methylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide;
• the compounds described herein may form salts with acids and/or bases, and such salts are included in the present invention.
• the salts are pharmaceutically acceptable salts.
• the term“salts” embraces addition salts of free acids and/or bases that are useful within the methods of the invention. Pharmaceutically unacceptable salts may nonetheless possess properties such as high crystallinity, which have utility in the practice of the present invention, such as for example utility in process of synthesis, purification or formulation of compounds useful within the methods of the invention.
• the disease is a fibrotic disease selected from the group consisting of idiopathic pulmonary fibrosis (IPF), myocardial infarction, cardiac hypertrophy, heart failure, cirrhosis, acetominophen (Tylenol) liver toxicity, hepatitis C liver disease, hepatosteatosis (fatty liver disease), and hepatic fibrosis.
• IPF idiopathic pulmonary fibrosis
• Myocardial infarction myocardial infarction
• cardiac hypertrophy heart failure
• cirrhosis acetominophen (Tylenol) liver toxicity
• hepatitis C liver disease hepatosteatosis (fatty liver disease)
• hepatic fibrosis hepatic fibrosis
• a non-limiting example of an effective dose range for a therapeutic compound of the invention is from about 1 and 5,000 mg/kg of body weight/per day.
• the pharmaceutical compositions useful for practicing the invention may be administered to deliver a dose of from 1 ng/kg/day and 100 mg/kg/day.
• One of ordinary skill in the art would be able to study the relevant factors and make the determination regarding the effective amount of the therapeutic compound without undue experimentation.
• the dose of a compound of the invention is from about 1 mg and about 2,500 mg. In some embodiments, a dose of a compound of the invention used in compositions described herein is less than about 10,000 mg, or less than about 8,000 mg, or less than about 6,000 mg, or less than about 5,000 mg, or less than about 3,000 mg, or less than about 2,000 mg, or less than about 1,000 mg, or less than about 500 mg, or less than about 200 mg, or less than about 50 mg.
• Formulations may be employed in admixtures with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable mode of administration, known to the art.
• the pharmaceutical preparations may be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and/or aromatic substances and the like. They may also be combined where desired with other active agents.
• the pharmaceutical composition of the invention can be formulated for administration to the eye of the subject with sustained release over a period of 3-12 months.
• short-term refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, about 10 minutes, or about 1 minute and any or all whole or partial increments thereof after drug administration after drug administration.
• the therapeutically effective amount or dose of a compound of the present invention depends on the age, sex and weight of the patient, the current medical condition of the patient and the progression of a disease or disorder contemplated in the invention. The skilled artisan is able to determine appropriate dosages depending on these and other factors.
• the compounds for use in the method of the invention may be formulated in unit dosage form.
• unit dosage form refers to physically discrete units suitable as unitary dosage for patients undergoing treatment, with each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier.
• the unit dosage form may be for a single daily dose or one of multiple daily doses (e.g., about 1 to 5 or more times per day). When multiple daily doses are used, the unit dosage form may be the same or different for each dose.
• reaction conditions including but not limited to reaction times, reaction size/volume, and experimental reagents, such as solvents, catalysts, pressures, atmospheric conditions, e.g., nitrogen atmosphere, and reducing/oxidizing agents, are within the scope of the present application.
• QC LC-MS Method 2 Waters SQD2, single quadrapole UPLC-MS.
• QC LC-MS Method 3 Acquity UPLC (binary pump/PDA detector) + Waters Micromass ZQ2000 Mass Spectrometer. Column: Acquity UPLC BEH C18 (1.7 ⁇ m, 100 ⁇ 2.1 mm), maintained at 40° C. Conditions: 0.1% aqueous formic acid [eluent A]; MeCN (containing 0.1% formic acid) [eluent B]. Gradient: 5 to 95% B over 6.8 min at 0.4 mL/min.
• starting materials are identified through a “Step” or“Example” number. This is provided merely for assistance to the skilled chemist.
• the starting material may not necessarily have been prepared from the batch referred to.
• Step 1 A solution of n-BuLi (1.2 eq.) was added dropwise to a stirred slurry of 8-chloro-3- methyl-imidazo[1,5-a]pyrazine (6.0 g, 35.8 mmol) at -78 oC in THF (to give 0.2 M solution) and the reaction mixture was stirred for 10 min. CO 2 was bubbled into the reaction mixture under stirring for 30 min. After removal of the solvent, the desired compound was purified using flash column chromatography to yield 5.3 g (70%) of 8-chloro-3-methylimidazo[1,5- a]pyrazine-5-carboxylic acid 1B.
• Example 20 3- ⁇ 4-[8-amino-3-ethyl-5-(piperazin-1-ylmethyl)imidazo[1,5-a]pyrazin-1- yl]naphthalen-1-yl ⁇ -1-[3-(trifluoromethyl)phenyl]urea
• Example 41 3- ⁇ 4-[8-amino-3-methyl-5-(1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,5- a]pyrazin-1-yl]naphthalen-1-yl ⁇ -1-[3-(trifluoromethyl)phenyl]urea, ES-LCMS m/z 558.7 (M+H).
• Example 44 3- ⁇ 4-[5-(1-acetylpiperidin-3-yl)-8-amino-3-methylimidazo[1,5-a]pyrazin-1- yl]naphthalen-1-yl ⁇ -1-[3-(trifluoromethyl)phenyl]urea, ES-LCMS m/z 602.6 (M+H).
• Example 46 3- ⁇ 4-[8-amino-5-(cyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1- yl]naphthalen-1-yl ⁇ -1-[3-(trifluoromethyl)phenyl]urea, ES-LCMS m/z 557.6 (M+H).
• Example 48 3- ⁇ 4-[8-amino-3-methyl-5-(pyridin-3-yl)imidazo[1,5-a]pyrazin-1- yl]naphthalen-1-yl ⁇ -1-[3-(trifluoromethyl)phenyl]urea, ES-LCMS m/z 553.7 (M+H).
• Example 52 3- ⁇ 4-[8-amino-5-(1,5-dimethyl-1H-pyrazol-4-yl)-3-methylimidazo[1,5- a]pyrazin-1-yl]naphthalen-1-yl ⁇ -1-[3-(trifluoromethyl)phenyl]urea, ES-LCMS m/z 569.3 (ES-).
• Additional compounds of the invention can be made according to the chemistry outlined in Scheme 5.
• iodo-intermediate 5B which can undergo Pd(0)-catalyzed coupling with vinyl or aryl boronates to give a coupling product such as 5C.
• 5E Bromination and reaction with ammonium hydroxide gives 5E which can undergo another Pd(0)-catalyzed coupling with aryl boronates to give 5F.
• Step 2 tert-Butyl (4-(8-chloro-3-isopropylimidazo[1,5-a]pyrazin-5-yl)cyclohex-3-en-1-yl) (methyl)carbamate 5C
• Example 57 2-(4-(8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin- 1-yl)naphthalen-1-yl)-N-(3-(trifluoromethyl)phenyl)acetamide
• Example 74 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5- a]pyrazin-1-yl)naphthalen-1-yl)-N-(thiazol-5-yl)acetamide
• Example 76 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5- a]pyrazin-1-yl)naphthalen-1-yl)-N-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)acetamide
• Example 78 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5- a]pyrazin-1-yl)naphthalen-1-yl)-N-(3,4-dimethoxyphenyl)acetamide
• Example 87 1-(4-(8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin- 1-yl)naphthalen-1-yl)-3-phenylurea
• Example 130 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1- yl)imidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl)-3-phenylurea
• Example 132 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1- yl)imidazo[1,5-a]pyrazin-1-yl)-3-methoxyphenyl)-3-(3-fluorophenyl)urea
• Example 138 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1- yl)imidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl)-3-(pyridin-3-yl)urea
• Example 142 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1- yl)imidazo[1,5-a]pyrazin-1-yl)naphthalen-1-yl)-3-(3-cyanophenyl)urea
• Example 143 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1- yl)imidazo[1,5-a]pyrazin-1-yl)naphthalen-1-yl)-3-(3,4-dimethoxyphenyl)urea
• Example 144 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1- yl)imidazo[1,5-a]pyrazin-1-yl)naphthalen-1-yl)-3-(pyridin-4-yl)urea
• Example 145 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1- yl)imidazo[1,5-a]pyrazin-1-yl)naphthalen-1-yl)-3-(4-fluorophenyl)urea
• Example 149 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1- yl)imidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl)-3-(5-fluoropyridin-3-yl)urea
• Example 161 1-(4-((4,6-difluoro-1H-benzo[d]imidazol-2-yl)methyl)naphthalen-1-yl)-3- isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-8-amine
• Example 167 1-(4-((7-chloro-1H-benzo[d]imidazol-2-yl)methyl)naphthalen-1-yl)-3- isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-8-amine
• Example 217 3-((4-(8-amino-3-isopropyl-1-(4-((7-methyl-1H-benzo[d]imidazol-2- yl)methyl)naphthalen-1-yl)imidazo[1,5-a]pyrazin-5-yl)cyclohex-3-en-1-yl)amino)-N,N- dimethylpropanamide Additional compounds of the invention can be made according to the chemistry outlined in Scheme 8.

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